Miguel Marcos

Systematic review with meta-analysis: the I148M variant of patatin-like phospholipase domain-containing 3 gene (PNPLA3) is significantly associated with alcoholic liver cirrhosis

Several studies have reported an association between alcoholic liver cirrhosis (ALC) or other forms of alcoholic liver disease (ALD) and the genetic variant rs738409 (C>G) in adiponutrin/patatin‐like phospholipase domain‐containing 3 gene (PNPLA3).

Chronic hepatitis B virus infection in Sjögren's syndrome. Prevalence and clinical significance in 603 patients

OBJECTIVE To analyze the prevalence and clinical characteristics of chronic hepatitis B virus (HBV) infection in a large series of patients with Sjögren syndrome (SS). METHODS We investigated the prevalence of chronic HBV infection in 603 consecutive patients with SS diagnosed in our department between 1994 and 2008. There were 517 patients with primary SS (482 women and 35 men, with a mean age at the time of fulfillment of the classification criteria of 57 years) and 86 patients with SS associated with chronic HCV infection (66 women and 20 men, with a mean age at the time of fulfillment of the classification criteria of 65 years). All patients fulfilled 4 or more of the 1993 European Community Study Group criteria for SS. RESULTS The presence of HBsAg+ was detected in five (0.83%) of the 603 patients with SS. All HBsAg+ patients had primary SS. No patient with HCV-related SS had HBV coinfection. There were 4 women and 1 man, with a mean age at diagnosis of primary SS of 65 years (range 31 to 89 years). All patients showed sicca and systemic involvement. The main extraglandular feature was articular involvement in 5 (100%) patients (including arthritis in two). The main immunologic features were RF in 4 (80%) patients and ANA in 3 (60%). No patient had hypocomplementemia, cryoglobulinemia, antimitochondrial or anti-LKM1 antibodies. Liver involvement was detected in two patients and consisted of slightly raised levels of transaminases. No patient showed clinical manifestations of liver disease such as hepatomegaly, splenomegaly, jaundice or clinical features of hepatic decompensation (ascites, encephalopathy or gastrointestinal bleeding). CONCLUSIONS We found a prevalence of chronic HBV infection of 0.83% in SS, very similar to the prevalence in general population in Spain (0.7%). In contrast to the close association between SS and HCV, chronic HBV infection is not associated with SS in our geographical area, with a ratio SS-HBV/SS-HCV cases of 1:10.

Some reasons why deletion and anergy do not satisfactorily account for natural tolerance

We would feel quite foreign to this Forum’s discussion on “deletion and anergy”, were it not for expressing our conviction that either “models or reality” of those phenomena are not the key to understanding the physiopathology of autoimmunity. Our position is not easy to define, for we do share the notion that V-region-dependent deletion of lymphocytes operates extensively in the normal immune system. Were we not the first, after all, to describe massive bone marrow pre-B/B cell deletion in normal mice (reviewed in Coutinho et al., 1992)? And are not our theoretical models constructed around the definition of lymphocyte physiology by “bellshaped” responses to receptor occupancy, with highdose inactivation (Coutinho, 1974; Varela and Coutinho, 1991)? We strongly object, however, to simplistic views that attempt to reduce natural tolerance to deletion and/or inactivation of self-reactivities, because we have also seen many examples of positively selected functional autoreactivities in normal animals, and quite a few cases of tolerance without deletion and/or anergy of the corresponding lymphocytes. From lymphocyte physiology, we also understand that if a particular ligand concentration presented to the continuous affinity distribution of an unselected repertoire leads to deletion or inactivation of some cells, it will necessarily activate some others. If negative and positive selection are the two sides of the same coin (repertoire selection by the molecular environment of lymphocytes that respond with “bell-shaped” profiles), it is a mistake to consider only the former in the context of natural tolerance (the physiological outcome of that selection). Beyond the molecular and cellular bases of repertoire selection, self-nonself discrimination has to deal with the “origin of the ligand”, and thus with its history in the organism. To us, “single cell solutions” of a problem that concerns organisms are bound to be incomplete, or wrong. In brief, natural tolerance is a developmental question, but one of organisms and not of single lymphocytes.

Val247Leu beta2-glycoprotein-I allelic variant is associated with antiphospholipid syndrome: Systematic review and meta-analysis

INTRODUCTION Previous studies have suggested that the possession of the Val/Val genotype of the Val247Leu polymorphism of the β(2)-glycoproteinI (β(2)-GPI) gene may be associated with antiphospholipid syndrome (APS), and, among patients with APS, with the production of anti-β(2)-GPI antibodies or the development of thrombosis. Given the controversial results reported, the aim of this work is to combine previous findings by means of a systematic review and a meta-analysis. METHODS We retrieved studies analyzing the genotype of the above-mentioned polymorphism among patients with APS by means of electronic database search. A meta-analysis was conducted in a random effects model and calculations of odds ratio (OR) and confidence intervals (CI) were done. Sensitivity analysis and tests for heterogeneity of the results were performed. RESULTS Eight previous studies analyzed the association of APS, anti-β(2)-GPI antibodies and/or thrombosis with the Val247Leu polymorphism. After meta-analysis, patients with APS had a significantly higher prevalence of the Val/Val genotype of this genetic variant when compared with controls (OR=2.04; 95% CI: 1.12, 3.73; P=0.02). Among patients with APS, those with anti-β(2)-GPI antibodies had a higher prevalence of this genotype (OR=1.73; 95% CI: 1.04, 2.87; P=0.03). No significant results were found for the presence of arterial or venous thrombosis. CONCLUSIONS Val/Val genotype of β(2)-GPI gene is associated with a significant excess risk to suffer from APS and, among patients with APS, to have anti-β(2)-GPI antibodies. No definite conclusions can be made regarding the association of this polymorphism with thrombosis among APS patients.

Meta‐analysis: glutathione‐S‐transferase allelic variants are associated with alcoholic liver disease

Aliment Pharmacol Ther 2011; 34: 1159–1172

Common polymorphisms in interleukin genes (IL4, IL6, IL8 and IL12) are not associated with alcoholic liver disease or alcoholism in Spanish men.

BACKGROUND Preliminary data suggest that polymorphisms in cytokine genes may be involved in the genetic predisposition to alcoholic liver cirrhosis or alcohol use disorders. We thus analyze the association between these diseases and the following polymorphisms: -33T>C IL4, -174 G>C IL6, -251 T>A IL8 and 1188 A>C IL12B. METHODS 258 male alcoholics (161 without liver disease and 97 with liver cirrhosis) and 101 healthy controls were genotyped for the above mentioned polymorphisms. We examined the relationship between genotype and allele frequencies and the presence of disease, as well as the correlation with combinations of putative pro-inflammatory genotypes. Haplotypes were inferred using the expectation-maximization algorithm and haplotype frequencies were compared. RESULTS We found no statistically significant association between any of these polymorphisms or the combinations of pro-inflammatory polymorphisms and the risk of alcoholic liver cirrhosis or alcohol abuse or dependence. Haplotype analysis of the IL4 and IL12B polymorphisms did not show any statistical relationship either. CONCLUSIONS Our results do not support the hypothesis that the analyzed polymorphisms confer differences in alcoholic liver cirrhosis or alcohol use disorders susceptibility.

Decreased peripheral blood CD4+/CD25+ regulatory T cells in patients with alcoholic hepatitis.

BACKGROUND Development of alcoholic hepatitis (AH) may be favored by the activation of the innate immune response. Recently, decreased numbers of circulating regulatory T cells (Tregs) have been reported in diseases associated with an immune activation status, but no studies have focused so far, in investigating the distribution of Tregs in chronic alcoholism and its potential association with liver disease. Here, we analyzed for the first time the frequency of peripheral blood (PB) Tregs and Treg subsets in AH and its relationship with the production of inflammatory cytokines by PB monocytes and dendritic cells (DCs). METHODS PB samples from 25 male patients with AH were studied; in parallel, 15 male chronic alcoholic patients without liver disease (AWLD) and 17 male healthy donors were also studied, as controls. The distribution of CD4⁺CD25hiCD127-/lo Tregs and their maturation subsets (naïve, central memory, and peripheral memory Tregs) was analyzed by flow cytometry. Spontaneous and in vitro-stimulated production of inflammatory cytokines by PB monocytes and DCs was analyzed by flow cytometry at the cytoplasmic level. RESULTS Patients with AH showed decreased (p < 0.05) numbers of PB CD4⁺CD25hiCD127-/lo Tregs at the expense of all maturation-associated subsets, while AWLD and healthy subjects showed a similar (p > 0.05) distribution of PB CD4⁺CD25hiCD127-/lo Tregs. Interestingly, significantly increased amounts of spontaneously produced inflammatory cytokines were found among circulating monocyte-derived DCs and monocytes from AH (and AWLD) patients in comparison with healthy donors. Conversely, the ability of these cell subsets to produce cytokines after in vitro stimulation was lower (p < 0.05) in AH versus the 2 control groups. CONCLUSIONS PB CD4⁺CD25hiCD127-/lo Tregs are significantly decreased in patients with AH when compared to both healthy and AWLD; this may contribute to explain the more pronounced activation of the innate immune response observed in AH, as reflected by an increased secretion of inflammatory cytokines by PB DCs and monocytes, and could facilitate the development of liver disease.

Adherence to Highly Active Antiretroviral Therapy in HIV-Infected Inmates

Adherence to highly active antiretroviral therapy (HAART) has been scarcely studied in correctional settings. Our study aims to evaluate the relationship between adherence and virological outcome and to determine factors related to adherence in correctional settings. A cross-sectional retrospective study was performed in Topas prison (Salamanca, Spain). 50 inmates starting HAART were studied. Adherence was estimated through a self-report questionnaire and variables related to adherence (covering individual factors, the illness itself and the therapeutic regimen) were recorded. HIV-RNA levels and CD4 lymphocyte count were measured before starting therapy and six months after. Statistical analysis was performed using univariate and multivariate methods. 21 inmates (42%) were considered adherent and 29 (58%) were non-adherent. Adherence to treatment, as measured by our questionnaire, was the only significant and independent factor associated with an undetectable viral load at six months of therapy. Five variables were significantly associated with adherence to treatment, four of them as predictor factors for good adherence: an active occupation inside prison, the absence of HIV-related symptoms, a good or average acceptance of treatment, and a higher academic background; previous injection drug use as a risk factor for HIV transmission was associated with non-adherence. A simple self-report questionnaire may be useful for assessing adherence in prison inmates. Recognizing variables associated with adherence is essential to identify prisoners at high risk of being non-adherents in order to develop strategies for improving compliance.

Factors Influencing Adherence to Highly Active Antiretroviral Therapy in Spain

BACKGROUND Multiple factors have been previously described which could influence adherence to HAART. Our objective is to determine the fundamental factors which influence adherence to highly active antiretroviral therapy in our population. METHODS A cross-sectional study was made selecting 143 outpatients attending our hospital HIV unit. 22 factors were recorded which could influence adherence to treatment (covering individual factors, the illness itself, the therapeutic regimen and the medical team). Adherence was estimated by the combination of two methods (self-report and pharmacy data); statistical analysis was performed using univariate and multivariate methods. RESULTS 96 patients (67.13%) had good adherence and 47 (32.87%) did not. Only 3 of the 22 factors studied were significant and independent factors related with adherence: employment, housing situation and degree of treatment acceptance. CONCLUSIONS we have found some differences regarding HAART adherence in our population compared with previous studies. Psychosocial and behavioral factors were the principal ones. We must try to detect patients at high risk of non-adherence in order to take therapeutic decisions properly, try to reinforce adherence and modify the factors associated with poor adherence.

p38γ and p38δ reprogram liver metabolism by modulating neutrophil infiltration.

Non‐alcoholic fatty liver disease (NAFLD) is a major health problem and the main cause of liver disease in Western countries. Although NAFLD is strongly associated with obesity and insulin resistance, its pathogenesis remains poorly understood. The disease begins with an excessive accumulation of triglycerides in the liver, which stimulates an inflammatory response. Alternative p38 mitogen‐activated kinases (p38γ and p38δ) have been shown to contribute to inflammation in different diseases. Here we demonstrate that p38δ is elevated in livers of obese patients with NAFLD and that mice lacking p38γ/δ in myeloid cells are resistant to diet‐induced fatty liver, hepatic triglyceride accumulation and glucose intolerance. This protective effect is due to defective migration of p38γ/δ‐deficient neutrophils to the damaged liver. We further show that neutrophil infiltration in wild‐type mice contributes to steatosis development by means of inflammation and liver metabolic changes. Therefore, p38γ and p38δ in myeloid cells provide a potential target for NAFLD therapy.